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Interactions of the Opioid and Cannabinoid Systems in Reward: Insights from Knockout Studies

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Interactions of the Opioid and Cannabinoid Systems in Reward: Insights from Knockout Studies REVIEW ARTICLE published: 05 February 2015 doi: 10.3389/fphar.2015.00006 Interactions of the opioid and cannabinoid systems in reward: Insights from knockout studies Katia Befort* CNRS, Laboratoire de Neurosciences Cognitives et Adaptatives – UMR7364, Faculté de Psychologie, Neuropôle de Strasbourg – Université de Strasbourg, Strasbourg, France Edited by: The opioid system consists of three receptors, mu, delta, and kappa, which are Dominique Massotte, Institut des activated by endogenous opioid peptides (enkephalins, endorphins, and dynorphins). The Neurosciences Cellulaires et Intégratives, France endogenous cannabinoid system comprises lipid neuromodulators (endocannabinoids), enzymes for their synthesis and their degradation and two well-characterized receptors, Reviewed by: Fernando Berrendero, Universitat cannabinoid receptors CB1 and CB2. These systems play a major role in the control of Pompeu Fabra, Spain pain as well as in mood regulation, reward processing and the development of addiction. Krisztina Monory, University Medical Both opioid and cannabinoid receptors are coupled to G proteins and are expressed Centre of the Johannes Gutenberg University, Germany throughout the brain reinforcement circuitry. Extending classical pharmacology, research using genetically modified mice has provided important progress in the identification of the *Correspondence: Katia Befort, CNRS, Laboratoire de specific contribution of each component of these endogenous systems in vivo on reward Neurosciences Cognitives et process. This review will summarize available genetic tools and our present knowledge on Adaptatives – UMR7364, Faculté de the consequences of gene knockout on reinforced behaviors in both systems, with a focus Psychologie, Neuropôle de Strasbourg – Université de on their potential interactions. A better understanding of opioid–cannabinoid interactions Strasbourg, 12, rue Goethe, F -67000 may provide novel strategies for therapies in addicted individuals. Strasbourg, France Keywords: opioid, cannabinoid, G protein-coupled receptors, reward, genetically modified mice e-mail: [email protected] INTRODUCTION Among illicit drugs, opiate and cannabinoid derivatives are Drug abuse often leads to a complex pharmaco-dependent state highly abused in Europe. Morphine-like opiates are powerful which is defined by the term addiction. Addiction is consid- analgesics and currently represent the major therapeutic reme- ered as a neuropsychiatric disease. It develops from an initial dies for the treatment of severe pain. They are also abused recreational drug use, evolves toward compulsive drug-seeking for their recreational euphoric effects. In Europe, 1.3 million behavior and excessive drug-intake with the appearance of nega- people are addicted to heroin, the primary drug for which tive emotional states such as anxiety or irritability when the drug treatment requests are sought. Cannabis is the most worldwide is not accessible, and uncontrolled intake reaching a stage where consumed drug of abuse, with THC being the most abun- the drug interferes with daily activities, despite the emergence dant active constituent found in the various preparations of of adverse consequences (Leshner, 1997; Everitt and Robbins, the drug. More than 73 million European citizens have used 2005; Robinson and Berridge, 2008; Koob, 2009). This patholog- cannabis in the last year and it is estimated that about 7% of ical process develops in 15–30% of casual drug users and several cannabis users has become dependent on this drug. There is also factors may explain individual’s vulnerability to addiction, includ- a high prevalence of users who seek treatment for dependence on ing genetic, psychological and environmental factors (Swendsen it (http://www.emcdda.europa.eu/publications/edr/trends-develo and Le Moal, 2011; Belin and Deroche-Gamonet, 2012; Pattij pments/2014). Interestingly, new derivatives of these abused drugs and De Vries, 2013; Saunders and Robinson, 2013). Addiction are invading the market, notably through internet. Fentanyl is a major threat to public health and represents a societal prob- derivatives as new opioid drugs and synthetic cannabimimetics, lem especially in developed countries and the economic cost it also known as “spices,” are becoming more and more popular entails (investments in research, treatment and prevention) is (Fattore and Fratta, 2011). These abusive substances interact with considerable (Gustavsson et al., 2011). two neuromodulator sytems, the opioid and the endocannabinoid systems. Abbreviations: 2-AG, 2-arachidonoylglycerol; AEA, anandamide, N-arachidonoyl- ethanolamide; CB1, type 1 cannabinoid receptor; CB2, type 2 cannabi- THE OPIOID SYSTEM noid receptor; cKO, conditional knockout mice; CPA, conditioned place The opioid system consists of endogenous opioid peptides aversion; CP 55,940, (1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]- (enkephalins, endorphins, and dynorphins) from precursors 4-(3-hydroxypropyl)cyclohexan-1-ol; CPP, conditioned place preference; CPu, caudate putamen; DA, dopamine; DAGL, diacylglycerol lipase; FAAH, (Penk, Pdyn, and Pomc) which activate three opioid receptors, fatty acid amide hydrolase; G protein, guanine nucleotide binding pro- namely mu, delta, and kappa (Kieffer, 1995). The three mem- tein; GABA, c-aminobutyric acid; GPCR, G protein coupled receptor; brane receptors, cloned in the early nineties (Evans et al., 1992; KO, knockout; MGL, monoacylglycerol lipase; NAPE-PLD, N-acyl phos- Kieffer et al., 1992; Simonin et al., 1994, 1995; Mestek et al., 1995) phatidylethanolamine phospholipase D; THC, Delta-9-tetrahydrocannabinol; WIN 55,212-2, 2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]- are GPCR with coupling to Gi/Go proteins, of which the 3D 1,4-benzoxazin-yl-1-naphtalenylmethanone mesylate; WT, wild-type. structure was recently resolved (see Filizola and Devi, 2014). www.frontiersin.org February 2015 | Volume 6 | Article 6 | 1 Befort Opioid and cannabinoid systems interaction in reward Opioid receptors and endogenous opioid peptides are largely energy balance, modulation of pain response, with processing of expressed throughout the nervous system, noticeably within areas central and peripheral pain signals, learning and memory, reward of the neurocircuitry of addiction associated with reward, motiva- and emotions. It has also been shown to be involved in neuroge- tion, or learning and stress (Mansour et al., 1995; Le Merrer et al., nesis and would play a neuroprotective role in some pathological 2009; Koob and Volkow, 2010; Erbs et al., 2014). Besides its key conditions (for recent reviews see Gardner, 2005; Solinas et al., role in many aspects of addition (Lutz and Kieffer, 2013a), the 2008; Maldonado et al., 2011; Zanettini et al., 2011; Panagis et al., opioid system also plays a part in a diverse range of physiological 2014; Piomelli, 2014). Distribution of the two receptors in the functions including nociception, mood control, eating behavior, central and peripheral system is rather different (Pertwee, 2010). or cognitive processes (Contet et al., 2004; Pradhan et al., 2011; Indeed, CB1 is highly abundant in the central nervous system in Stein, 2013; Bodnar, 2014; Nogueiras et al., 2014). areas involved in reward, regulation of appetite and nociception (see Figure 1) while CB2 was initially described as a peripheral THE ENDOCANNABINOID SYSTEM receptor (Maldonado et al., 2006, 2011; Mackie, 2008). Recent The endocannabinoid system is a neuromodulatory system con- studies have proposed a low but significant expression of this sisting of two well characterized transmembrane receptors coupled receptor in several brain structures including striatum, hippocam- to G protein (Gi/Go), CB1, and CB2 cloned in the 1990’s (Mat- pus, and thalamus (Wotherspoon et al., 2005; Gong et al., 2006; suda et al., 1990; Munro et al., 1993). The endogenous ligands Onaivi et al., 2006) and more recently into ventral tegmental area are lipid neuromodulators, the main ones being AEA and 2-AG. neurons (Zhang et al., 2014). Only few data are therefore available Both are synthesized from phospholipid precursors and act locally for the CB2 receptor in central function but growing evidence sug- as retrograde regulators of synaptic transmission throughout the gest a role in addictive processes, with an implication in cocaine, central nervous system. These lipids are released by postsynaptic nicotine, or ethanol effects (Xi et al., 2011; Ignatowska-Jankowska neurons and mainly activate presynaptic cannabinoid receptors to et al., 2013; Navarrete et al., 2013; Ortega-Alvaro et al., 2013). To transiently or persistently suppress transmitter release from both our knowledge, no data is available thus far concerning a potential excitatory and inhibitory synapses (recently reviewed in Ohno- role of CB2 in opioid mediated responses. Interestingly, other Shosaku and Kano, 2014). Multiple pathways are involved in AEA non-CB1 and non-CB2 receptors have been proposed to interact biosynthesis with several still not fully characterized enzymes. with endocannabinoids like the orphan GPCR GPR55 or a channel AEA can be generated from the membrane phospholipid precur- vanilloid TRPV1 recognizing capsaicin. These interactions could sor N-arachidonoyl phosphatidylethalonamine (NAPE) through a potentially explain some pharmacology of cannabis that cannot two-step process with first a calcium-dependent transacylase fol- be accounted for by CB1 and CB2 activation, but further studies lowed by a phospholipase
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